Increasing context and focus of ‘epidrugs’

A growing body of evidence has proved the ability HDAC inhibitors (HDACi) to exert anti-cancer actions in many tumor systems. Currently, HDACi are extensively used to sensitize tumor cells for treatment with chemotherapy. The main disadvantage of HDACi is the broad inhibition of the HDAC-containing complexes. This might also apply to additional chromatin modulators, which target different enzymes than HDACs. A couple of recent studies suggest possible solutions-strategies to render epidrugs more focused or more context-dependent.

For example, in acute promyelocytic leukemia (APL) the PML-RARα oncofusion protein operates a repression, which is mediated by HDAC-containing complexes. This repressive action can be dissociated by pharmacological doses of retinoids (ATRA), inducing differentiation and cell death at the expense of side effects and recurrence. De Bellis and co-authors (Cancer Res., 2014) hypothesize that the context-specific close physical proximity of a retinoid and HDACi binding protein in the repressive PML-RARα-HDAC complex may permit selective targeting by a hybrid molecule of ATRA with the aminoanilide tail of entinostat. This study and the mechanistic insights therein may provide proof-of-principle of the concept of a context-dependent targeted therapy. With a different focus, Rotili and coauthors (J. Med. Chem., 2014) reflected on the fact that in prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed and colocalize with the androgen receptor. Thus they designed hybrid LSD1/JmjC or “pan-KDM” able to simultaneously target both KDM families. These types of molecules seem to display high antitumor actions in solid cancer cells.

Both studies represent molecularly based, hypothesis-driven approaches to render epigenetic-based treatments more targeted and-or context-selective. In the future these approaches might shed new light into the use of epidrugs.